Soluble MICA-NKG2D interaction upregulates IFN-γ production by activated CD3CD56 NK cells: Potential impact on chronic graft versus host disease

A soluble isoform of MHC class I chain-related molecule A (soluble MICA), generated by proteolytic shedding from the membrane-bound MICA of various tumor cells, has been shown to downregulate both the expression of natural killer group 2-member D receptor and the cytotoxic function of effectors cells and was postulated as a mechanism for tumor immune evasion. Its effect on the expression of cytokines by the effector cells remained unexplored. Here we demonstrate that the sMICA molecules upregulate interferon gamma expression by interleukin-12/interleukin-18-activated CD3⁻CD56⁺ natural killer cells, witnessing the pro-inflammatory effect of soluble MICA. Overall, these data are in line with our previous observations that the raised serum levels of soluble MICA, following allogeneic hematopoietic stem cell transplantation, confer susceptibility to and the presence of pre-transplantation anti-MICA antibodies in the patient’s serum confer protection against chronic graft versus host disease.     

Reframing resilience: Strengthening continuity of patient care to improve the mental health of immigrants and refugees

Refugee and immigrant populations experience many pre‐ and post‐migration risk factors and stressors that can negatively impact their mental health. This qualitative study aimed to explore the system‐level issues that affect the access to, as well as quality and outcomes of mental health care for immigrants and refugees, with a particular focus on challenges in the continuity of patient care. A multidisciplinary group of health providers, including nurses, identified six themes including (i) perceived access to care; (ii) coordination amongst health care providers; (iii) patient connections with community organizations; (iv) coordinated care planning; (v) organizational protocols, policies and procedures and (vi) systemic and health care training needs. Although patient resilience is seen as a pivotal way for vulnerable populations to cope with hardship, there is a clear need for creating a resilient health care system that is able to anticipate and adapt to adverse situations. The findings from this study have implications for nurses, who are uniquely positioned to advocate for public health policy that improves the continuity of health care by creating systemic resilience.     

Insulin-like Growth Factor Messenger RNA-binding Protein 3 Expression Helps Prognostication in Patients with Upper Tract Urothelial Carcinoma

Background

Upper tract urothelial carcinoma (UTUC) is a clinically heterogeneous disease that lacks high-quality trials that provide definitive prognostic markers. Insulin-like growth factor messenger RNA binding protein 3 (IMP3) has been associated with outcomes in urothelial carcinoma of the bladder but was not yet studied in UTUC.

Objective

To evaluate the association of the oncofetal protein IMP3 with oncologic outcomes in patients with UTUC treated with radical nephroureterectomy (RNU).

Design, setting, and participants

We investigated the expression of IMP3 and its association with clinical outcomes using tissue microarrays constructed from 622 patients treated with RNU at seven international institutions between 1991 and 2008.

Intervention

All patients were diagnosed with UTUC and underwent RNU.

Outcome measurement and statistical analysis

Uni- and multivariable Cox regression analyses evaluated the association of IMP3 protein expression with disease recurrence, cancer-specific mortality, and all-cause mortality.

Results and limitations

IMP3 was expressed in 12.2% of patients with UTUC (n = 76). The expression was tumor specific and correlated with higher stages/grades. Within a median follow-up of 27 mo (interquartile range [IQR]: 12–53), 191 patients (25.4%) experienced disease recurrence, and 165 (21.9%) died of the disease. Patients with IMP3 demonstrated significantly worse recurrence-free survival (27.4% vs 75.1%; p < 0.01), cancer-specific survival (34.5% vs 78.9%; p < 0.01), and overall survival (15.6% vs 64.8%; p < 0.01) at 5 yr compared with those without IMP3. In multivariable Cox regression analyses, which adjusted for the effects of standard clinicopathologic features, IMP3expression was independently associated with disease recurrence (hazard ratio [HR]: 1.87; p < 0.01), cancer-specific mortality (HR: 2.15; p < 0.01), and all-cause mortality (HR: 2.07; p < 0.01). Major limitations include the retrospective design and relatively short follow-up time.

Conclusions

IMP3 expression is independently associated with disease recurrence, cancer-specific mortality, and all-cause mortality in UTUC. IMP3 may help improve risk stratification and prognostication of UTUC patients treated with RNU.     

Hematopoietic MicroRNA-126 Protects against Renal Ischemia/Reperfusion Injury by Promoting Vascular Integrity

Ischemia/reperfusion injury (IRI) is a central phenomenon in kidney transplantation and AKI. Integrity of the renal peritubular capillary network is an important limiting factor in the recovery from IRI. MicroRNA-126 (miR-126) facilitates vascular regeneration by functioning as an angiomiR and by modulating mobilization of hematopoietic stem/progenitor cells. We hypothesized that overexpression of miR-126 in the hematopoietic compartment could protect the kidney against IRI via preservation of microvascular integrity. Here, we demonstrate that hematopoietic overexpression of miR-126 increases neovascularization of subcutaneously implanted Matrigel plugs in mice. After renal IRI, mice overexpressing miR-126 displayed a marked decrease in urea levels, weight loss, fibrotic markers, and injury markers (such as kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin). This protective effect was associated with a higher density of the peritubular capillary network in the corticomedullary junction and increased numbers of bone marrow–derived endothelial cells. Hematopoietic overexpression of miR-126 increased the number of circulating Lin⁻/Sca-1⁺/cKit⁺ hematopoietic stem and progenitor cells. Additionally, miR-126 overexpression attenuated expression of the chemokine receptor CXCR4 on Lin⁻/Sca-1⁺/cKit⁺ cells in the bone marrow and increased renal expression of its ligand stromal cell-derived factor 1, thus favoring mobilization of Lin⁻/Sca-1⁺/cKit⁺ cells toward the kidney. Taken together, these results suggest overexpression of miR-126 in the hematopoietic compartment is associated with stromal cell–derived factor 1/CXCR4-dependent vasculogenic progenitor cell mobilization and promotes vascular integrity and supports recovery of the kidney after IRI.Ischemia/reperfusion injury (IRI) is a central event in such clinical conditions as AKI and in organ transplantation, and it is strongly associated with delayed graft function and long-term graft survival.^1–3 Emerging evidence indicates that the renal microvascular endothelium of the outer medullary peritubular network is the primary site of injury in the pathogenesis of ischemia-induced renal dysfunction.⁴ Following ischemia, perfusion of the peritubular capillary network is rapidly impaired as a consequence of endothelial cell (EC) swelling,⁵ impaired vasorelaxation,⁶ and increased leukocyte adhesion.⁷ In addition, microvascular destabilization initiated by the loss of EC–EC interaction⁸ and EC–pericyte interactions can lead to significant reductions in peritubular capillary density due to microvascular rarefaction.^8,9 The resulting loss in renal perfusion can further exacerbate medullary ischemia and drive the development of interstitial fibrosis by stimulation of profibrogenic factors, such as TGF-β.¹⁰ As a consequence, integrity of the peritubular capillary network is a key determinant for the preservation of renal function. Indeed, clinical biopsy studies have shown an association between loss of tubular structure and function on the one hand and capillary rarefaction on the other.^11,12Because of their limited replicative capacity, renal ECs are thought to be insufficiently capable to completely repair the injured endothelium of the peritubular capillary plexus after IRI.^13,14 Therefore, current therapeutic strategies to prevent microvascular loss have focused on the prevention of pericyte perturbation to reduce capillary rarefaction.^15–18 However, once rarefaction has occurred, these strategies may fail to induce sufficient revascularization required to reverse renal dysfunction.¹⁹ In search of ways to augment neovascularization in the injured kidney, many laboratories have investigated the biology and therapeutic use of circulating vascular progenitor cells originating from the bone marrow (BM) compartment.²⁰ These progenitor cells were shown to incorporate into the injured microvasculature in experimental models for GN,²¹ ischemic nephropathy,^22,23 and interstitial fibrosis.²⁴ This phenomenon has been particularly observed when extensive or repetitive endothelial injury occurs, for example in kidney transplantation.²⁵ Microvascular incorporation of BM-derived progenitor cells has been linked to preservation of the vasculature because they may serve as an alternative cellular source to facilitate re-endothelialization.²⁶ In addition, the CXCR4⁺ fraction of progenitor cells is mobilized to the ischemic kidney by local secretion of the chemokine stromal cell–derived factor-1 (SDF-1)^23,27 and has been shown to exert renoprotective effects in a paracrine fashion.Phosphoinositide 3-kinase (PI3K)/AKT signaling in progenitor cells plays a critical role in mobilization of progenitors from the BM via the SDF-1/CXCR4 axis²⁸ and their subsequent differentiation toward vascular cells.²⁹ MicroRNA-126 (miR-126) is a key regulator of PI3K/AKT signaling by direct targeting of the negative regulator PI3K regulatory subunit 2 (PI3KR2/p85-β) and targets genes that play key roles in angiogenesis and inflammation.^29–31 In addition, miR-126 was shown to coregulate the expansion and mobilization of hematopoietic stem cells and progenitor cells.^32,33 We hypothesized that miR-126 overexpression in the hematopoietic compartment of mice can enhance the vasoprotective potential of these progenitors and that this will translate to decreased renal injury.